SU591149A3 - Method of preparing derivatives of triazoloisoquinoline - Google Patents

Description

carbon atoms; by reacting the compound with the general formula Q where Sj R has the indicated meanings, with a compound of the general formula "2 (f) where R has the indicated meanings; Group 1, cf. , ORjV TS. exSBj Ш UH, ITftt where R. is alkyl with 1–3 carbon atoms at 60–160 ° C in the presence of an acidic catalyst, the compound obtained is the general formulas where R, R, and Pd have the indicated values, cyclizing by boiling in an organic solvent in the presence of a strong base, followed by isolation of sprouts or, in the case when the A-group is CH-CH, dehydrogenate the resulting compound. nothing Both reagents, compounds of general (P) and (III) g, can be used as bases or as corresponding salts or base salts. Thus, a compound of the formula f y) can be used as e-hydrochloride, while a compound of the formula (| P), if it is thiocyanic acid, can be used in its alkali metal salts, or if I is an imido ester It can be used in the form of its hydrochloride. The proposed method can be carried out either as a two-stage process with isolation of the compound of formula (W) or without isolation of the latter. GTdpo is a selection of intermediate products form: (1), which {a.1e have pharmacological activity and can be used in medicine. Condensation of the 2-amine -3,4-dihydroisoquivolin of the formula Yu) with the compound of the formula (III) carried out by heating for hours at 60-160 ° C, preferably using an excess of reagent (formula). The reaction is carried out in the presence of acidic substances, preferably hydrogen halide, introduced into the reaction mixture. The most convenient use of the compound of formula (ijl) as the catalyst of the hydrogen halide of the reactant. For example, the reaction is carried out by heating 1 mol of 2-amino-3,4-dihydroisohyNolinon-1 with 1.5 mol of ethyl ester) benzimidic acid and 0, 1 mol of chlorohydrate of this ester. Condensation is preferably carried out under vacuum. The reaction mixture containing 2-Bionosimidoylamino-3, 4-dihydro-isoquinolinone-1 of formula 05) I is dissolved, for example, in an alkanol, where alkyl with 1-4 carbon atoms, is added a basic catalyst, for example, 0.5 mol a strong base such as sodium hydride or an alkali metal alcoholate, where alkyl is from 1-4 carbon atoms, and is refluxed for 3-8 hours. The desired products are recovered by conventional methods, such as evaporation of the solvent, dissolution of the solid residue in non-. a water-miscible organic solvent; washing the solution with water, evaporating the organic phase, followed by crystallization of the residue or chromatography on a column. In order to isolate the intermediate compound of formula (5), the reaction mixture of the condensation stage is washed with an aqueous solution of sodium bicarbonate and water, and evaporated, followed by crystallization of the residue from evaporation. It is better to use imide as the compound of formula (III), cyanamides, proi. aqueous cyanic and thiocyanic acids. By dehydrating the obtained compounds, compounds are obtained, where A is the CH-CH group. Sulfur, N-bromadetamide, bromine, lead tetraacetate, mercury acetate, chloranil, dichlorodicyanoquinone and manganese dioxide can be used as dehydrating agents. The reaction is carried out in the presence of a solvent, preferably an inert organic, for example, benzene, dioxane tetrahydrofuran, tetrahydrofuran, and the like. The dehydrating agent may be added in the same amount as the triazoloisoquinolium compound or in

corresponding to a molar excess if manganese dioxide is used.

After the reaction is completed and the catalyst is removed by filtration, the resulting solution is evaporated to dryness, to obtain a residue, which can immediately be cleaned with known methods, for example column chromatography, by distillation in vacuo if the residue is a liquid, or by recrystallization from an appropriate solvent. case of solid product.

The proposed method gives better yields than the yield of 2-phenyl-simm-triazolo (for example, by isoquinoline 66% (for 2-amino-3,4-dihydroisoquinolinone), which is known, for example, by the target method), while the yield of this compound 35% (for 1-aminoisoquinoline), 2-methi / δ-5,6-dihydro-sim-triaalo 5, -a isoxynnoline is obtained by the targeted method with a total yield of 85% on 2-amino-3,4-dihydro- 1 (2I) -isoquinolinone, while using the well-known method, the yield of this compound is 25% (per 1-aminoisoquinoline). The remaining compounds are new.

The resulting compounds can also be converted to their acid addition salts, which are obtained by reacting the base with the corresponding acid. Preferred salts include salts of mineral acids, for example hydrochloride, bromoyllate, sulfate, phosphate, etc., and salts of organic acids, such as succinate, benzoate, acetate, p -toluenesulfonate, benzrlsulfonate, maleate, tartrate, methanesulfonate, cyclohexyl sulfonate, and the like.

PRI me R 1. 2- (m-methoxyphenyl-5,6-

-dihydro-symm-triazolo 5, .1-a isoquinoline.

A mixture of 16.5 g of 2-amino-3,4-dihydro-1 (2H) -isoquinoline (0.1O mol), 27 g

m-methoxybenzimidic acid ethyl ester (o, 15 mol) and 2.15 g ethyl ester hydrochloride of this acid are heated for 5 hours under vacuum h / 20 O mm Hg) at and 2 h at 125 ° C, then 3.50 g is added m-methoxybenzimidic acid ethyl ester (0.02 mol), the mixture is heated for another 16 hours at 125 ° C under vacuum. All volatiles were removed by distillation at 125 ° C / 5 mm Hg. The solid residue can be used without purification for cyclization or after washing with aqueous sodium bicarbonate and water can be very crystalline from ethanol to isolate - intermediate - 2 - (- methoxybenzimidoyl amino) - -3,4-dihydro-1 (2H) isoquinolone m.p. 176-177 ° C. The crude reaction product is cyclized by boiling under reflux for 5 hours in 150 ml of ethanol containing 1.2 g (o, 040 mol) of 8O% sodium hydride. The mixture is evaporated to dryness in vacuo, dissolved in methylene chloride, the organic solution is washed with water and evaporated, the residue is crystallized from 5O% ethanol and obtain 2O g (72%) of the title compound, m.p. 94-96 C.

The cyclization of the purified intermediate product can be carried out in accordance with the method described above.

Examples 2-31. The interaction of 2-amino-3,4-dihydro-1 (2H) -isoquinolinone with ethyl imidate in the presence of its hydrochloride as in Example 1 gives 2-B-5,6-dihydro-simm-triazole 5, 1-a isoquinolines. In the table, primer's imidic acid, substituent B in position 2, constants of isoquinolines obtained, and so on. the corresponding intermediate imidoylaminoisoquinolinones.

2- (o-todil)

o-toluimidna

2- (m-tolunl)

m-toluimidna

2- (p-toluyl)

c-Toluimidna

2-4en

Benzimide

2- (o-chlorophenyl)

o-chlorobenzimide

2- (m-chlorophenyl)

m-chlorobenzimide

39

87 81

236-237 203-204 83 206-2О7 54

235-236.jpg..,

2 - (- cyclopentrum

M-Cyclopentyloxyphenyl) oxybenzimide

2 - ((l-allyloxyM-allyloxybenzophenyl) imide

2- (m-propagyloxy-A-proparloxy and phenyl) benzimidium

54

76-78

78

96-97

71

113-114 k, -egoxyphenyl) 1O2-SW3 2- (m propoEns to nyl) 2- (m-benzyl oxyphenyl) 2-. (3,4-methylenedioxyphenyl) 2- (4-4TIR dil) - (m- fluoromethylphenyl) 2- (m-fluorophenate1) 2- (3,4-dimethylphenyl) 2- (m-isoproxyphenyl) 2- (4-pentiloxyphenyl) 116-117 112-113 147-148 72 246-248 158-159 60197- 198 147-148 63208-210 105-106 143-144 1О6-1О7

I-fluorobeneimide

Propionimidna Vaperimidna

(Butoxibeneimide Example 32. 2 Amino-simk.triazslo 5,1-a and eoquinolin. A mixture of 28 g of 2-amino-3,4-α-dihydro-1 (2H) -isoquinoline hydrochloride (0.142 iMoab) and 6.25 g of cyanamide (OD49 mol) in 27 O m of the free acetonitrile is boiled for 2 hours under reflux, cooled, and the precipitated precipitate is isolated by filtration. The resulting 2-guanidino-3,4-dihydro-1 (2H) -isoquinolinone hydrochloride recrystallized isohydrate from ethanol, mp 261 ° C (decomp.), and added to 17.4 g of 97% hydroxide. Sodium in 700 ml .8O% ethanol, the mixture is boiled for 7 hours under reflux, the solvent distilled off in vacuum The remaining residue is dissolved in water, the pH of the mixture is adjusted to 7 with acetic acid. The precipitated solid product is filtered and 23.4 g (89%) of the title compound are obtained with a mp of 164-165 ° C (from ethanol). , 6-dihydro-simm-tria ash 5, isoquinoline. A mixture of 3.24 g of 2-amino-3,4-dihydro-1 (2H) -isoquinolinone (0.02 mol), 3.2 ml of formamide (0.08 mole) and 0.02 i Q piperidine acetate is heated for 15 hours at 140, after which the volatiles are distilled off in vacuo. The residue is dissolved in 10 ml of ethanol, then 0.1 g of 80% sodium hydride is added to the solution and the mixture is heated under reflux for 5 hours. The solvent is evaporated to dryness, and the solid residue is extracted with several portions of boiling hexane. The obtained organic solution (25 ml) was kept in a refrigerator for two days, then the precipitated solid product was removed.

Continue tabs

72

) 121-122

81

63-65 75 135 / 0.05

80

61-63 are filtered, and 1 g (30%) of the desired product is obtained, m.p. 84-85 ° C. Example 34. 2-Mercapto-5,6-digDr. ro-simm-triazolo j 5, l-a) isoquinoline. To 1.98 g of 2-amino 6-3,4-dihydro-1 (2H) -isoquinoline hydrochloride (0.01 mol) was added 0.97 g of sodium thiocyanate (0, O1 mol) in 5 ml of water at room temperature. temperature and 5 minutes stirred, cooling the mixture to O C. The solid is washed with cold water, then heated to 14 ° C. in an open reaction vessel for 20 minutes, the mixture is cooled, the solid residue is crystallized from Ethanol and 1.7 g (81%) 2 is obtained -thiureido-3,4-diGydro-1 (2H) | -shzokhinolinona so pl. 225 С, 0.66 g of which (О, ООЗ mol) is heated for 18 hours with reflux condenser with О, О99 g of 8О% sodium hydride (о, ООЗЗ mol) in 10 ml of isopropanol. By evaporation of the solvent, a solid is obtained, which is dissolved in water, after which the solution is acidified to pI5 with acetic acid. The solid precipitate is isolated by filtration, recrystallized from 80% ethanol, and 0.45 g (74%) of the title compound is obtained, m.p. 2 36-23 8 ° C. Pr and measures 35. 8,9-Dimethoxy-2- (K1-, methoxyphenyl) 5,6-dihydro-symm-triazm-5, 1-a1 isoquinoline. The compound was prepared analogously to example 1 of 2-amino-5,6-dimethoxy-3,4-dihydro-1 (2H) -isoquinoline and methoxybenzimidic acid ethyl ester, m.p. 132JL33. ° C,

11 IT r iur 36. 8 “. Mvtoksi-2- (k“ -sifonil labels) -5,6-drgidro-snmm-triazopo, l-aj and iaozshnopin. The compound was prepared analogously to example 1 of 2a-6-methoxy-3,4-digiaro-1 (2H and a-oxyquinoline of methoxybenzimidic acid ethyl ester, m.p. with m-triaaolo 5,1-a isochnolyn 35 g of wet manganese dioxide were suspended in 2 pO ml of benzene and the mixture was boiled under reflux for 3 hours, then a solution of 2.77 g was added (O, O 10 mol) 2- (m-methoxyphenyl) -5,6-dngydro-sym-triazolo, 5,1-a iaoquinoline in 30 ml of absolute benzene, boil for another 6 hours with reflux condenser, and then stand overnight add 20 g wet dv manganese oxides, "the resulting suspension & h is boiled under reflux. After cooling, the solid catalyst is filtered off, 9 is released, the benzene solution is dried in vacuum, the resulting residue is recrystallized from ethyl acetate, yield 1.4 g, mp. 15 9-16 0 ° C. According to another variant, the target compound can be obtained with a yield of 7 0% by treating with 1.5 M of sulfur at 200–250 ° C., Example 38. 2–4 enyl-Sim | -triazolo 5, 1-and isoquinoline. Under the conditions of Example 37 and starting from 2-4}) enyl-5,6-digi-dro-Simm-triazolo 5,1-a isoquinoline, the desired compound was obtained, yield 56%, mp. 1S7-158 C (from ethyl acetate). I ... Example 39. 2.-Phenyl.-Simm triazo-. lo 5,1-a} isoquinoline. A mixture of 0.5 g (0.002 mol) of 2-phenyl-5, 6-digi of dro-simm-triazolo T 5,1-a isoquinoline and 0.28 g (0.002 mol / N-bromoacetamide in 10 ml of carbon tetrachloride Ksh tt 5 under reflux, the resulting crystalline precipitate is filtered and dissolved in methylene chloride, then washed with sodium bicarbonate, the solvent is evaporated, the residue obtained is recrystallized from ethyl acetate, yield 79% mp 159-16l C. The following compounds are obtained by analogous methods : 2- (p-methoxyphenyl) -5,6-dihydro-symm-tri-zolo1 5,1-a1 isoquinoline ;, 2- (o-methoxyphenyl) -5,6-dihydro-symm-three , la isoquinoline; 2- (m-cycloprproxyphenyl) -5,6-dihydro-symmetric triazolo | 5,1-a isoquinoline; 2- (m-Ciclobutoxyfennl) -5,6-dihydro-sim triazolo | 5,1 - a yzohinolin;

12 2- (m ". Of 6 butoxyphenyl) -5,6-digi-diro-sim triazolo 5,1-аЗ isoquinoline; (tre-butoxy) -pheny; 5th iiro | imm-triaolo 5, 1-a isoquinoline; 2- (m-isoamyloxyphenyl) -5,6-dihydro-simmtriazolo 5,1-aJisoquinoline; - (m-1hcclohexyloxyphenyl; -b, dihydro; imm-triazolo 5,1-a isoquinoline; 2- (2- "iridyl-5,6-digi dro-simm-triazole 5, la isoquinoline; 2- ( 2,6-Dimetip-4-nrididno-5,6-dihydro-SI | If. Triaolo (5,1-isoquinoline; 2- (2-methi; 1-4-41 iryl) -5,6-dihydro-siik triazolo, 1-aTisoquinoline; 2 - (- ethynfeiyl / -5,6-dihydro-simm-tripiazol 5, 1-a isoquinoline; 2- (m-isobutiphenyl) - 5,6-dihydro-simm-triazolo 5, 1- and isoquinoline; 2- (m-fluorophenyl) -siml-triazolo 5,1-aJ isoquinoline; 2- (m-benaoyloxyphenyl) -Sym-triazolo {5,1-a isoquinoline; 2- (m-ethoxyphenyl) -oim -triazolo 5,1-a iso quinoline; 2- (m. allyloxyphenyl) triazolo 5,1 isoquinoline; 2- (m-prop rgiloks1 "|) enyl) -symm triazolo | 5,1-a) iaoquinoline; 2- (3,4-methylenedioxyphenyl).-symm-triazolo 15,1-a isoquinoline; 2- (m-propoxyphenyl) -sym-triazolo 5,1-aj isoquinoline; 2- (m-cyclopropoxyphenyl) .- simk..triazolo 5,1-a isoquinoline; 2- (m-isoproxyphenyl) -sym-triazolo (5,1isoquinoline; 2- (wU-cyclobutoxyphenyl) β-sym-triazole o 5, la isoquinoline; 2- (m-cyclopentyloxyphenyl) -sym1-triazolo 15, la isoquinoline; 2- (m-bu topiphenyl) -symm-triazolo 5,1-a isoquinoline; 2-m- (t-butoxyphenyl) -symm-triazolo 5,1-a isoquinoline; 2 :-( t1-dimethylaminophenyl.) - SIMm-triazolo 5,1-aZisoquinoline; 2- (p-fluorophenyl) -symm-triazolo {5,1-a isoquinoline; 2- (p-chlorophenyl) -. Symm-triazolo 5, quinoline; 2- (m pentyloxyphenyl) -symm-triazole 5,1 isoquinoline; 2- (m-cyclohexyloxyphenyl) -symm-triazole, 1-a isoquinoline; 2- (m-isoamyloxyphenyl). - simm-triazole 5,1 isoquinoline; 2- (2,6-dimethyl-4-pyridyl) -symm-trnazole 5,1-a isoquinoline; 2- (m-ethylphenyl) -syM1-triazole 5,1-a isoquinoline.

13

Formula and method of obtaining derivatives of triazoloisoquine

-n where A is the group СЬ-СН or СI-СИ; R is hydrogen, amuta, mercapto group, alkyl with 1 carbon atoms,) rO | v methyl, unsubstituted sludge mixed with 1-2 methyl groups, pyridyl, unmixed phenyl, phenyl, substituted with aldyl with 1-4 carbon atoms, alkoxy , alkenyloxene, alkynyloxy group, in which alkyl, alhenyl or alkynyl with 1-4 carbon atoms, halogen, trifluoromethyl, methylene dioxy, cyclopropyloxy, cyclobutyloxy, diclopentyloxy, diclohexyloxy or benzyloxy, dialkylamino or nitro group; RJ and RJ independently of each other are hydrogen or alkoxy, where alkyl with 1-4 carbon atoms, 1ta based on aminoisoquinoline derivatives, and tl and h and so that, in order to increase the yield, simplify the process and diversification, derivatives of aminrizokhinolin general formula. O wherein RJ and Rj have the indicated meanings, they are reacted with a compound of the general formula IIII where R has the indicated meanings; 2 - group W, cG. with

/ Srj

with

,

in

where P, - lkil with 1-3 atom A5I carbon,

at 60-160 ° C in the presence of ACID 0

catalyst, the resulting compound of the general formula omi 11-I CMN, where R, Rj and Rj have the indicated signs, are boiled in an organic solvent in the presence of a strong base, followed by isolation of an absurd product or, in the case when A is the group CH- CH, dehydrating the resulting compound. Priority by the following signs: 25.05.73 with A - CH3-SI group, R hydrogen, amino-, mercaptogrunea, alknl with 1-4 carbon atoms, trifluoromethyl, non-interfered or replaced 1st 1-2 methyl group of pyridyl, non-substituted phenl or phenyl substituted by alkyl with 1–4 carbon atoms, alkrhenium, and kenyloxy, alkynyloxy, in which alkyl, alkenyl, or alkynyl with 1–4 carbon atoms, halogo, trifluoromethyl, methylbredioxy, cyclopropyloxy, cyclobutylshs, piclopentyloxy, cyclohexyloxy or benzyloxy, dialkylamino or nitro, P, K K „is a breed; 22.08.73 for A - the SI-CH group, Sources of information, to take into account in the examination: 1. Reimeinget N. et a, Synthesen lind eactitonen der S-Fi toizofotS, 1 oi isochtnoPin. Thetn. Bef., 1971, vof.104, $. 3965.